First Author | Chen JX | Year | 2017 |
Journal | Toxicol Sci | Volume | 155 |
Issue | 1 | Pages | 224-233 |
PubMed ID | 27664423 | Mgi Jnum | J:257718 |
Mgi Id | MGI:6102126 | Doi | 10.1093/toxsci/kfw190 |
Citation | Chen JX, et al. (2017) From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells. Toxicol Sci 155(1):224-233 |
abstractText | In the past decades, experimental rodent models developed to study the pathogenesis of human colorectal cancer (CRC) generally employed synthetic chemical carcinogens or genetic manipulation. Our lab, in order to establish a more physiologically relevant CRC model, recently developed a colon carcinogenesis model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS)-induced colitis in the cytochrome P450 1A-humanized (hCYP1A) mice. The resulting colon tumors shared many histologic and molecular features of human colon cancer. In this study, we characterized the early stages of PhIP/DSS-induced colon carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the colon mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas. Molecular analysis of the early time-points (ie, days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/beta-catenin mutations and beta-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent normal tissues. In addition, we investigated the role of Lgr5+ colon stem cells in the PhIP/DSS-induced colon carcinogenesis and found the presence of Lgr5-enhance green fluorescent protein-expressing cells amidst some ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5+ stem cells in this dietary carcinogen-induced, inflammation-promoted colon carcinogenesis model. Overall, the findings suggest that PhIP/DSS-induced colon carcinogenesis is likely initiated by dominant active Ctnnb1/beta-catenin mutation in residual epithelial cells, which when promoted by colitis, developed into high-grade dysplasia and adenocarcinoma. |